Microcystins are Peptide hepatotoxins produced by cyanobacteria present in water bodies including portable water supplies, constituting an environmental public health hazard. Okadaic acid and related compounds are the toxic components causing diarrheic shellfish poisoning through the consumption of contaminated shellfish. The mode of action of okadaic acid and microcystins is the potent, specific inhibition of the ser/thr protein phosphatases 1 and 2A. Even a modest degree of phosphatase inhibition in hepatocytes results in impaired microtubule-dependent transport, membrane trafficking, and receptor-mediated endocytosis, with increased phosphorylation of several components of the microtubule-based motor protein, cytoplasmic dynein. Our thesis is that in liver, changes in the phosphorylation of the dynein complex cause changes in motor activity. This translates into impaired membrane trafficking, affecting essential cellular/organ functions like endocytosis and transcytosis.
The specific aims of this proposal are: 1) How is the phosphorylation of cytoplasmic dynein and associated polypeptides regulated? 2) How do changes in phosphorylation of cytoplasmic dynein and associated proteins contribute to changes in dynein activity ? What is the mechanism for these effects? 3) Do changes in the phosphorylation and activity of the cytoplasmic dynein complex lead to altered endocytic membrane traffic? Completion of these studies will increase our knowledge of basic liver function as well as provide insights into the long term consequences for chronic low dose ingestion of these toxins through the water supply or elsewhere. Disruption of membrane traffic because of motor and/or MT changes, be they genetic or environmental, will cause impaired hepatic function and disease. A better knowledge of the control of the components involved in traffic as proposed in this application will lead to novel therapeutic strategies in the event of toxicological or pathophysiological liver damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056040-03
Application #
6381569
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (01))
Program Officer
Serrano, Jose
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$256,786
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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